Abstract
Introduction: Inactivating mutations of the calcium-sensing receptor (CASR) gene result in neonatal severe hyperparathyroidism (NSHPT). Total parathyroidectomy is an effective way to control life-threatening hypercalcemia in NSHPT but leads to permanent hypoparathyroidism. An alternative surgical option is subtotal parathyroidectomy. However, few cases were reported in the literature. Here, we report two unrelated NSHPT patients, one with a novel homozygous mutation (c.1817T>C; p.Leu606Pro) in CASRand the other with heterozygous for the same mutation who also carried two rare intronic variants in CASR. The outcomes of subtotal parathyroidectomy in these patients are also described. Case Presentation: Two infants presented with an alteration of consciousness, respiratory distress, and bradycardia. Severe hypercalcemia, hypophosphatemia, and markedly elevated parathyroid hormone levels were identified, suggesting NSHPT. Cinacalcet was unable to control calcium (Ca) levels of both patients. A novel heterozygous and homozygous missense mutation c.1817T>C; p.Leu606Pro was identified in patients 1 and 2, respectively. Based on the model prediction, proline substitution at Leu606 is likely to disrupt conversion between the active and inactive conformations at the extracellular to transmembrane domain interface of CASR. In addition, two extremely rare intronic variants in CASR (chr3:g.122180314A>G and chr3:g.122251601G>A, based on GRCh38) were identified in patient 1 and his mother. These variants might have contributed to the clinical manifestations of patient 1 who was heterozygous for the c.1817T>C; p.Leu606Pro variant. Subtotal parathyroidectomy was performed by removing three and a half parathyroid glands. So far, patient 1 has been in normocalcemia for 5 years. Patient 2 was in normocalcemia for 16 months after surgery and subsequently developed mild hypoparathyroidism which required only low-dose calcitriol treatment. Conclusion: We report a novel heterozygous and homozygous missense variant (c.1817T>C; p.Leu606Pro) in CASR in two NSHPT patients. The mutation likely disrupts conformational changes of CASR and results in cinacalcet unresponsiveness. Intronic variants in CASR identified in the patient with heterozygous variant might have contributed to the clinical manifestations of the patient. Although total parathyroidectomy is widely accepted as a standard treatment for NSHPT, we demonstrate that subtotal parathyroidectomy is also an effective procedure to normalize Ca levels and allow these patients to be in normocalcemia or mild hypoparathyroidism, which is simply controlled by low-dose calcitriol treatment. Subtotal parathyroidectomy appeared to be an effective treatment for NSHPT regardless of the molecular etiologies.
